Mutations in a broad sense include all those heritable changes which alter the phenotype of an individual. The term mutation was first used by Hugo de Vries; thus characterizing phenotypic changes as separate from environmental variations. However, the term mutation, as it is used now refers to only those changes that alter the chemical structure of the gene at the molecular level. These mutations are usually called point mutations. Theoretically it may be easy to differentiate structure changes and mutations, but it is not so easy at the molecular level. This is because some structural changes may have the same phenotypic effects as gene mutations. Hence, scientists use cytology to differentiate between the two. Also, gene mutations are able to give reverse mutations.

The earliest record of point mutation was in 1791 when Seth Wright noticed a lamb with unusually short legs in his flock of sheep. He bred an entire flock of these short legged sheep and realized that individuals with short legs were homozygous recessive. He confirmed his results by perform a back cross.

Mutations can be artificially induces with the help of mutagenic agents which are of two types- physical mutagens and chemical mutagens. Physical mutagens are radiations, change in pH etc. Ionizing radiations like X rays and gamma rays are the main physical mutagens. There use in radiation therapy, nuclear reactors has made us prone to radiation exposure. Acute or chronic exposure to highly penetrable irradiation like gamma rays can be lethal if not treated immediately. Chemical mutagens like Mustard Gas, MMS, EMS, and DMN have been used since the beginning of world war II for their delayed mutagenic effect. Scientists like C. Auerbach are credited to be the pioneers in this field.

The molecular mechanism for mutation depends greatly on the type of mutagen. Physical mutagens like ionizing radiations are primarily known to cause thymine dimerisation. They may also be responsible for backbone breakage, depurination etc. Chemical mutagens cause a wider variety of chemical changes in the DNA molecule- incorporation of base analogues, inhibition of nucleic acid precursors, changing the nucleic acid resting state structure. All these chemical reactions alter the reactivity of the purine and pyrimidines molecule and therefore the DNA.

Due to the seriousness of the effects of mutagens and the threat of lethal mutations, scientists all over the world are working on radiation counter measure agents while focusing on compounds with antioxidant properties.

Mutation is a permanent change in the sequence of DNA that makes up a gene is known as mutation. Mutations may vary in size from single DNA base to a large fragment of a chromosome. Let us focus on different types of mutation, starting with substitution.
Substitution
A type of mutation wherein a single nucleotide is exchanged for or substituted with a different nucleotide that alters the amino acid sequence in translation rendering ineffective newly synthesized protein is known as substitution. One example of is substitution of purine with another purine (A → G) or a pyrimidine with another pyrimidine (C → T). This type of substitution is also known as transition. Another kind is transversion in which a purine with pyrimidine or a pyrimidine with a purine is substituted. Mutations due to substitution replaces one base with another. Due to redundancy in genetic code some substitutions may not pose any effect at all. As, for example a uracil substitution for a cytosine in the CCU codon does not impart any effect on the protein synthesised as both CCC and CCU code for proline. On the other hand, depending on the region of substitution in the amino acid chain a substitution replacing the amino acid with another may vary widely in the effect that might occur.
For example a substitution producing AUG (the stop codon) is the most serious one as it will prematurely end an amino acid chain. Changes that cause a lesser effect on the configuration of protein does not dramatically affect the protein function. Mutation in an individual that occurs due to single base substitution may have significant consequences. As, for example, sickle cell anemia, which is a serious disease occurs due to mutation from single base substitution. A point mutation of the β- globin gene in codon 6 results in the substitution of glutamic acid by valinethereby causing sickle cell anemia. β-globin is an important component of haemoglobin (HbA). Amino-acid substitution results in HbS type of haemoglobin, with different properties from the normal HbA. In certain conditions like low oxygen tension following exercise or lesser oxygen content of the atmosphere, the following changes occur:(1) Agglutination of the hemoglobin, forming insoluble rod-shaped polymers;
(2) Distorted sickle –shaped red blood cells
(3) Rupture of the sickle-shaped cells, causing haemolytic anemia;
(4) Blockage of capillaries due to sickle shaped cells, causing interference with the blood flow to the organs.
Another disease caused by substitution mutation is thalassemia. In this case the in codon 39 a single base substitution of C by U form of a stop signal UAG in place of glutamate and a shortened globin chain having only 39 amino acids in the β-globin chain of protein instead of the normal 146. This protein is not functionally active getting equivalent to absence of β-globin thereby causing medical symptoms of thalassemia.

After discussing substitution in detail, let us consider an insertion type of mutation in detail. Insertion mutation is the insertion or addition of nucleotide base pairs into a sequence of DNA, thereby making it longer than the usual length. For example, if a DNA sequence reads CAGC and a T is inserted between G and C during the copying of the sequence, it would then read CAGTC. This is a mutation due to insertion. This mutation could be detrimental if it occurs in a gene, or the region of a DNA sequence coding for a protein, resulting in the formation of a nonfunctional protein.
Certain inherited human disorders occur from insertion of several copies of the same nucleotide triplets. Some of the diseases caused from trinucleotide repeat are Huntington's disease and the fragile X syndrome. These disorders are caused by the genetic inheritance wherein insertions of 3 to 4 nucleotides repeated over and over. In human a locus on X chromosome consists of such stretch of nucleotide in which CGG triplet is repeated (CGGCGGCGGCGG, etc.). If these repeats are in a noncoding region of the gene then it may not cause any harmful phenotype. Even 100 or more repeats cause no harm. But, these long stretches of nucleotide repeat may grow longer from one generation to the other may be up to 4000 repeats, which causes a constriction region on the X chromosome making it quite fragile. Males inheriting such X chromosome from their mothers possess quite a number of harmful phenotypic effects such as mental retardation. Males with the syndrome rarely become fathers. However, females inheriting such a fragile X chromosome also from their mothers only mildly get affected.
In another disorder Polyglutamine Diseases, the trinucleotide repeat CAG adds a string of glutamines to the protein encoded. These types of mutation are implicated in several disorders related to central nervous system that including:
• Huntington's disease: Here the protein known as Huntingtin carries the extra string of glutamines. The abnormal protein resulted from insertion increases the p53 protein level in the brain cells, thereby causing death due to apoptosis.

• Certain cases of Parkinson's disease wherein the extra string of glutamines is inserted to the encoded protein ataxin-2.
• Certain forms of muscular dystrophy appearing in adults are due to the formation of trinucleotide or tetranucleotide repeats, e.g. (CTG)n and (CCTG)n, where n may be up to thousands. Due to the formation of the large RNA transcript interference of the alternative splicing of other transcripts occurs.[/align]

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